HDAC inhibitors (HDACI) are promising anti-tumor agents that have just entered the clinics. Despite their potent activity, the fundamental question of how HDAC inhibitors achieve their anti-tumor effects remains poorly understood. It is not known which of the HDAC family members or which cellular pathway is the most critical target for the antitumor activity of HDACI. This knowledge would facilitate the development of more effective inhibitors that target specific HDAC member(s) and identify the pathway(s) critical for HDACI to kill tumors, thereby aiding in the rational design of future cancer therapy. We have discovered that inactivation of a single HDAC member, HDAC10, recapitulates all major effects of HDACI, including growth arrest, cell death, induction of a cell cycle inhibitor, and reactive oxygen production (ROS). We further showed that HDAC10 inactivation and HDACI treatment both dramatically activate autophagy, a cellular response intimately linked to metabolic stress and cell death. These findings strongly suggest that HDAC10 is a key target mediating the anti-tumor activity of HDACI. Remarkably, we found that HDAC10 is localized to mitochondria. We hypothesize that HDACI elicits anti-tumor effects by targeting the mitochondrial deacetylase HDAC10, which controls mitochondrial function and autophagy important for tumor cell growth and proliferation. Specifically, we propose: